Method for obtaining pure enantiomers of a pyridazinone derivative

ABSTRACT

The present invention relates to a method for preparing optically active enantiomers of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile (I), particularly (−) enantiomer of (I). Furthermore, the invention relates to a novel crystalline polymorphic form of the (−) enantiomer.

This is a 371 of PCT/F197/00196 filed on Mar. 27, 1997.

TECHNICAL FIELD

The present invention relates to a method for preparing optically activeenantiomers of[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile(I), particularly (−) enantiomer of (I). Furthermore, the inventionrelates to a novel crystalline polymorphic form of the (−) enantiomer.

BACKGROUND OF THE INVENTION

The racemic mixture of[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile(I) has been described earlier in the applicant's European Patent No.38:3449 B1. It was shown that compound (I) is potent in the treatment ofcongestive heart failure and has significant calcium dependent bindingto troponin.

Optically active enantiomers of (I) have been earlier described in theapplicant's European Patent No. 565546 B1. It was shown that thecardiotonic potency is predominantly due to the (−) enantiomer of (I). Amethod for preparing pure (−) enantiomer of (I) using optically pure (−)enantiomer of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone(II) as an intermediate compound was also disclosed.

The racemic compound (II) can be synthesized by methods known in theliterature (J. Med. Chem., 17, 273-281 (1974)). The resolution of theracemic compound (II) has, however, been proved very difficult becausethe 4-amino group in the molecule is weakly basic. The salts of6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone with opticallyactive acids hydrolyse on crystallization readily back to the compound(II) and to the resolving compound which interfere the resolutionprocedure or make it totally impossible.

The separation of the pure enantiomers of compound (II) on a chiralHPLC-column has been described in European patent application No.208518. This method is, however, not applicable for industrial scale. Anenantioselective seven step synthesis of(−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone startingfrom (+)-2-chloropropionic acid has also been described in theliterature (J. Org. Chem., 56, 1963 (1991)). The total yield in thismethod is only 12% giving(−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone with anoptical purity of 97.2%.

In the above mentioned European Patent No. 565546 B1 it was found thatthe racemic intermediate (II) can be resolved by treating (II) with L-or D-tartaric acid in excess in 2-propanol and recovering thediastereomeric crystalline salt. Optical purity of the product wasfurther increased by dissolving the recovered basified product indioxane. The racemic residue was crystallized from dioxane and thefiltrate was evaporated to dryness yielding the desired pure enantiomerof the intermediate (II). The pure (−) enantiomer of (I) was prepared bytreating (−) enantiomer of the intermediate (II) further with sodiumnitrite and malononitrile in acidic conditions as described in the abovementioned European Patent No. 383449 B1.

Even if this process gives pure (−) enantiomer of (I), the necessity touse harmful dioxane limits its applicability in the large scale.Therefore there is a need for an improved process for preparing pure (−)enantiomer of (I).

DESCRIPTION OF THE DRAWINGS

FIG. 1 is the X-ray powder diffraction pattern in 3-33 2θ° range of thepolymorphic form I of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]hydrazono]propanedinitrile

SUMMARY OF THE INVENTION

It has now been found that substantially pure (−) enantiomer of (I) canbe prepared more conveniently and without dioxane if the resolution isconducted in two different synthesis stages. The initial resolution stepcomprises resolving racemic intermediate (II) and the final resolutionstep comprises resolving the enantiomerically enriched end product (I).It was also found that the initial resolution step results in higheroptical purity of intermediate (II) if ethyl acetate is used as solventinstead of 2-propanol. Furthermore it was found that the minor componentin a partly enriched enantiomer mixture of end product (I) can becrystallized out from acetone.

Thus the present invention provides a method for preparing opticallysubstantially pure(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]hydrazono]propanedinitrilethe method comprising the steps of

a) resolving racemic6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone byprecipitation with a resolving acid in the presence of a solvent,

b) treating the recovered6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone which isenriched in (−) enantiomer with sodium nitrite and malononitrile,

c) allowing the resulting[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrilewhich is enriched in (−) enantiomer to contact with acetone,

d) removing the precipitate,

e) recovering from the mother liquid of step d) the opticallysubstantially pure(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrileby crystallization.

Furthermore the present invention provides a method for preparingoptically substantially pure(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrilethe method comprising the steps of

a) suspending[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]hydrazono]propanedinitrilewhich is enriched in (−) enantiomer in acetone solvent,

b) removing the precipitate,

c) recovering from the mother liquid of step b) the opticallysubstantially pure(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrileby crystallization.

The present invention also provides a method for the optical resolutionof racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinonewhich method comprising the steps of

a) contacting the racemic mixture with D- or L-tatraric acid in ethylacetate solvent,

b) recovering the crystalline salt; and

c) optionally basifying the salt to form the corresponding free base.

Furthermore the present invention provides a novel crystallinepolymorphic form I of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]hydrazono]propanedinitrileand methods for the preparation thereof.

DETAILED DESCRIPTION

The term “optically substantially pure” means here optical purity overabout 90%, preferably over 95%, and more preferably over 99%, expressedas the percent enantiomeric excess. The terms “resolve” and “resolution”are intended to compass the complete or partial separation of the twooptical enantiomers.

According to the present invention the racemic compound (II) ispreferably resolved by reacting the racemic mixture of (II) with D- orL-tartaric acid in ethyl acetate solvent. Advantageously the ethylacetate solvent contain from 0 to about 6 w-%, preferably from 2 to 4w-%, more preferably about 3 w-%, of water. It is preferred to use D- orL-tartaric acid and compound (II) in about equimolar amounts. Thediastereomeric salts of (−)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone withD-tartaric acid or corresponding (+)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone withL-tartaric acid crystallize from ethyl acetate in good yield. Thecrystalline diastereomeric salt can be filtered and the free baseliberated by basifying the salt with e.g. potassium carbonate solutionor ammonia. The mother liquid can be recovered after filtering and befurther treated in order to recover the enantiomer which was notpreviously removed by precipitation. The treatment may comprise e.g.cooling the mother liquid and recovering the resulting crystallinediastereomeric salt.

Typically the product obtained by the above described method containsabout 90 w-% of the desired enantiomer of (II). The purity of theproduct can be increased to about 96 w-% by recrystallization.Acetonitrile is the preferred recrystallization solvent. For example,the product which is enriched in (−) enantiomer is recrystallized byadding the product to acetonitrile solvent, refluxing the mixture andfiltering precipitate. The filtrate is concentrated, if necessary, andcooled in order to crystallize the (−) enantiomer of (II).

By way of comparison it can be noted that the resolution method of EP565546 B1 which comprises treating (II) with L- or D-tartaric acid inexcess in 2-propanol yields a product containing less than 70 w-% of thedesired enantiomer of (II) if the product is not further treated withdioxane.

Partial resolution of compound (II) can be obtained, as shown by theExamples, using other solvent systems than ethyl acetate. Such solventsinclude isopropanol, isobutanol, isopropyl acetate, butyl acetate,acetone and acetonitrile. Also the use of other resolving acids than D-or L-tartaric acid can result in partial resolution of compound (II),e.g. benzoic acid or sulphuric acid. However, the method of using D- orL-tartaric acid in ethyl acetate or aqueous ethyl acetate solventprovides the highest optical purities for compound (II) according to theinvention.

The end product(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile(I) is prepared from6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone intermediate(II) which is enriched in (−) enantiomer by allowing the intermediate toreact with sodium nitrite and malononitrile in acidic conditions asdescribed in EP 383449 B1. Compound (I) which is enriched in (−)enantiomer is then recovered.

It has been found that the minor component in a partly enrichedenantiomer mixture of compound (I) can be filtered out from acetoneleaving the rest of the major component in solution. This allowsrecovering the substantially pure (−) enantiomer of (I) from the mothersolution by crystallization.

Thus, in order to prepare substantially pure (−) enantiomer of (I) thepreviously recovered compound (I) which is enriched in (−) enantiomer issuspended in acetone solvent, which preferably contains up to 2 w-% ofwater. The mixture is refluxed and the precipitate is filtered. Thefiltrate is then concentrated, if necessary, and cooled to about 0-(−5)°C. The precipitated crystalline (−) enantiomer of (I) is recovered. Theproduct contains typically more than 99 w-% of the desired (−)enantiomer of (I) and is therefore suitable for use as a medicament.

The enantiomeric purities of the products were determined by the highperformance liquid chromatography (HPLC,). The enantiomers of compound(II) were separated by using a cellulose-type chiral column (ChiralcelOJ 25×0.46 cm). The mobile phase consisted of ethanol. The flow rate was0.5 ml/min. The enantiomers of compound (I) were separated by using aβ-cyclodextrin column (Cyclobond I Beta, 4.6×250 mm). The mobile phaseconsisted of 36% methanol in water buffered to pH 6.0 with 1%triethylammonium acetate. The flow rate was 0.8 ml/min.

It was furthermore discovered that the above described methods ofpreparing substantially pure (−) enantiomer of (I) yield a novelcrystallographically pure polymorphic form of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile,herein designated, for convenience, as polymorphic form I. The importantadvantage of the polymorphic form I is its high dissolution rate inwater. This makes the polymorphic form I especially useful inpharmaceutical preparations of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile.

It was also found that the crystallographical purity of the polymorphicform I can be, if necessary, improved by heating the obtained (−)enantiomer product at a temperature of at least about 70° C. for a timeperiod necessary for the formation of crystallographically purepolymorphic form I. The suitable temperature is typically within therange of 70-160° C., preferably 80-130° C. The time period is typicallywithin the range of 1-48 h, preferably 4-24 h. This treatment may bepart of the drying process of the product and may be carried out invacuum.

The polymorphic form I of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrileis characterized by the X-ray crystallography. The X-ray powderdiffraction pattern of the polymorphic form I in 3-33 2θ° range is inFIG. 1 and the crystallographic data in Table 1.

The diffraction pattern was measured by the X-ray powder diffraction(XRPD) equipment, Siemens D 500 (Siemens AG, Karlsruhe, Germany). Acopper target X-ray (wavelength 0.1541 nm) tube was operated with thepower of 40 kV×40 mA. For X-ray powder diffraction analysis the sampleswere mounted by loosely pressing about 500 mg of the powder to thespecific cylindrical sample stage which has a diameter of 20 mm andheight of approximately 2 mm. Mathematical evaluation of diffractionpatterns was performed with aid of Diffrac AT V3.1 software package.Main characteristics of the diffraction patterns as 2θ-values andrelative peak intensities were produced as out-put data.

TABLE 1 X-ray diffraction angles (2θ°) and corresponding relativeintensity values (only %-values ≧5%) of polymorphic form I. Relativeintensity 2θ angle(°) (%)  8.7  5  9.5 23 12.2 34 15.4 25 15.9 40 17.772 18.4  8 19.2  9 20.3 27 21.4  8 21.8  8 23.1 36 24.6 12 25.7 100 27.4 64

The relative intensity values may vary remarkably because of differentorientation of crystals. Therefore, the relative intensity values givenin Table 1 can be regarded as representative only for, e.g.non-micronized powder.

The following examples are meant to further illustrate the invention.

EXAMPLE 1 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

100 g of racemic6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone was added to2997 ml of ethyl acetate, 94,4 ml of water, 77,8 g of D-tartaric acidand 1.0 g of D-tartaric salt of(−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone undernitrogen. The mixture was stirred in room temperature for 1.5 h.Thereafter the mixture was heated to 65° C. and stirred for 2 h. Theprecipitate was filtered hot and washed with 561 ml of ethyl acetate.The precipitate was mixed with 400 ml of water and pH of the mixture wasadjusted to 9-10 with NH₃. The mixture was cooled to 0° C. and stirredfor 2 h. The precipitate was filtered, washed three times with 322 ml ofcold water and dried in vacuum in 50° C. Yield was 35 g and the ratio of(−/+) enantiomers 93/7%. The product (35 g) was further added to 777 mlof acetonitrile and 2.0 g of celite under nitrogen. The precipitate wasfiltered hot and washed with 33 ml of acetonitrile which was added tothe filtrate. 253 ml of acetonitrile was distilled from the filtrate andthe remaining mixture was cooled to −5° C. The precipitate was filtered,washed with 76 ml of acetonitrile and dried in vacuum in 50° C. Yield24.5 g. Ratio of (−/+) enantiomers 96/4%.

EXAMPLE 2 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

50 g of racemic6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone was added to1500 ml of ethyl acetate, 46 ml of water, 37.5 g of D-tartaric acid and1.0 g of D-tartaric salt of(−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone. Themixture was stirred in room temperature for 1.5 h. Thereafter themixture was heated to 65±3° C. and stirred for 3 h. The precipitate wasfiltered hot and washed with 116 ml of ethyl acetate of roomtemperature. The precipitate was mixed with 200 ml of water of roomtemperature and 44 g of potassium bicarbonate in 90 ml of water wasslowly added. It was checked that pH was over 9.0. The mixture wascooled to 0±3° C. and stirred for 2 h. The precipitate was filtered,washed three times with 120 ml of cold water and dried in vacuum in50±5° C. Yield 17.87 g. Ratio of (−/+) enantiomers 90.7/8.6%.

EXAMPLE 3 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

50 g of racemic6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone was added to1500 ml of ethyl acetate, 45 ml of water and 37.3 g of L-tartaric acid.The mixture was heated to 60° C. and stirred for 2 h. The precipitatewas filtered and the filtrate was cooled to −10° C. and kept in thistemperature for 2 h. The precipitate that crystallized from the filtratewas filtered and dried in vacuum in 50° C. The precipitate was mixedwith 200 ml of water in room temperature and 43 g of potassiumbicarbonate in 90 ml of water was slowly added. It was checked that pHwas over 9.0. The mixture was cooled to 0° C. and stirred for 2 h. Theprecipitate was filtered, washed three times with 120 ml of cold waterand dried in vacuum in 50±5° C. Yield 20.61 g. Ratio of (−/+)enantiomers 78.7/21.2%.

EXAMPLE 4 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

1 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinonewas added to 30 ml of isopropanol and 0.6 g of benzoic acid. The mixturewas boiled until dissolved and cooled to room temperature whereupon theproduct crystallized. The crystalline product was filtered and the ratioof the benzoic acid salts of the enantiomers was determined. Ratio of(−/+) enantiomers 74.1/25.5%.

EXAMPLE 5 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

1 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinonewas added to 30 ml of isopropanol and 0.48 g of concentrated sulphuricacid. The mixture was boiled and cooled to room temperature. Thecrystalline product was filtered and the ratio of the sulphate salts ofthe enantiomers was determined. Ratio of (−/+) enantiomers 65.1/34.9%

EXAMPLE 6 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

5 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinonewas added to 75 ml of ethyl acetate, 3.1 ml of water and 3.73 g ofL-tartaric acid. The mixture was boiled for 3.5 h, the precipitate wasfiltered and the filtrate was cooled to −10° C. The precipitate thatcrystallized from the filtrate was filtered and dried in vacuum in 50°C. Yield 2.86 g. The ratio of the L-tartrate salts of the enantiomers(−/+) 72/27%.

EXAMPLE 7 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

1 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinonewas added to 20 ml of isobutanol and 0.75 g of L-tartaric acid. Themixture was boiled and cooled. A sample was taken as soon as thecrystallization started (at 64° C). The ratio of the L-tartrate salts ofthe enantiomers (−/+) 53/46%. 0.6 ml of water was added to the mixture,the mixture was boiled, cooled and a sample was taken at the beginningof the crystallization (at 64° C.). The ratio of the L-tartrate salts ofthe enantiomers (−/+) 60/40%. Again 0.6 ml of water was added to themixture and the previous procedure was repeated. The product startedcrystallize at 46° C. The ratio of the L-tartrate salts of theenantiomers (−/+) 56/44%.

EXAMPLE 8 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

1 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinonewas added to 60 ml of isopropyl acetate and 0.75 g of L-tartaric acid.The mixture was boiled and a sample was taken from the undissolvedprecipitate. The ratio of the L-tartrate salts of the enantiomers (−/+)44/56%. 1.2 ml of water was added to the mixture, whereupon theprecipitate dissolved. The mixture was cooled and a sample was taken atthe beginning of the crystallization (at 68° C.). The ratio of theL-tartrate salts of the enantiomers (−/+) 24/76%.

EXAMPLE 9 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

1 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinonewas added to 50 ml of ethyl acetate, 0.75 g of L-tartaric acid and A)0.5, B) 1.0 or C) 1.5 ml of water. The mixture was boiled and cooled.The mixture was filtered and a sample was taken from the precipitate andfrom the filtrate at the beginning of the crystallization. The ratio ofthe L-tartrate salts of the enantiomers (−/+) %:

Precipitate Filtrate Crystallization temperature, ° C. A) 29/71 66/30 52B) 22/77 65/32 54 C) 20/80 85/13 50

EXAMPLE 10 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

1 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinonewas added to 50 ml of butyl acetate and 0.75 g of L-tartaric acid. Themixture was boiled and cooled. The mixture was filtered and a sample wastaken from the precipitate at the beginning of the crystallization (64°C.). The ratio of the L-tartrate salts of the enetntiomers (−/+) 44/55%.

EXAMPLE 11 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

1 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinonewas added to 10 ml of acetone and 0.75 g of L-tartaric acid. The mixturewas warmed until dissolved (54° C.) and cooled to 0° C. A sample wastaken from the precipitate. The ratio of the L-tartrate salts of theenantiomers (−/+) 49/42%.

EXAMPLE 12 (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

1 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinonewas added to 44 ml of acetonitrile and 0.75 g of L-tartaric acid. Themixture was boiled and cooled. A sample was taken from the precipitateat the beginning of the crystallization. The ratio of the L-tartratesalts of the enantiomers (−/+) 43/50%.

EXAMPLE 13(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile

The 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone obtainedin Example 2 with (−/+) resolution % of 96/4 was treated with sodiumnitrite and malononitrile as described in the European Patent No. 383449B1. 10 g of the recovered[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrilewith (−/+) resolution % of 96/4 was added to 150 ml of acetone, 0.9 mlof water, 0.2 g of activated carbon and 0.4 g of Celite. The mixture wasrefluxed for 1 h and filtered hot. The precipitate was washed with 10 mlof hot acetone which was added the to the filtrate. The filtrate wasrefluxed for 30 min. 61 ml of acetone was distilled from the filtrateand the remaining mixture was cooled to 0-(−5) ° C. The mixture wasfiltered and washed with 10 ml of cold acetone. The crystalline productwas dried in vacuum in 50° C. The product contained over 99% of thedesired (−) enantiomer and the yield was 6.8 mg. The product wassubstantially pure crystalline polymorphic form I.

EXAMPLE 14 (−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile

The title product was prepared as in Example 13 except that the dryingwas carried out in 100° C. for 5 h. The product was pure crystallinepolymorphic form I.

EXAMPLE 15 (−)-[[4-(1,4,5,6-tetrahydro-4-methy-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile

The title product was prepared as in Example 13 except that the dryingwas carried out in 120° C. for 18 h. The product was pure crystallinepolymorphic form I.

What is claimed is:
 1. A method for preparing optically substantiallypure(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrilecomprising the steps of a) resolving racemic6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone byprecipitation with a resolving acid in the presence of a solvent, b)treating the recovered6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone which isenriched in (−) enantiomer with sodium nitrite and malononitrile, c)allowing the resulting[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrilewhich is enriched in (−) enantiomer to mix with acetone, d) removing theprecipitate, e) recovering from the mother liquid of step d) theoptically substantially pure(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrileby crystallization.
 2. The method according to claim 1 wherein thesolvent is ethyl acetate, isopropanol, isobutanol, isopropyl acetate,butyl acetate, acetone or acetonitrile.
 3. The method according to claim2 wherein the solvent is ethyl acetate.
 4. The method according to claim3 wherein the solvent comprises up to 6 w-% of water.
 5. The methodaccording to claim 1, wherein the resolving acid is D- or L-tartaricacid.
 6. A method for preparing optically substantially pure(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrilecomprising the steps of a) suspending[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]hydrazono]propanedinitrilewhich is enriched in (−) enantiomer in acetone solvent, b) removing theprecipitate, c) recovering from the mother liquid of step b) theoptically substantially pure(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrileby crystallization.
 7. The method according to claim 6 wherein theacetone solvent comprises up to 2 w-% of water.
 8. The method for theoptical resolution of racemic6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone which methodcomprising the steps of a) reacting the racemic mixture with D- orL-tatraric acid in ethyl acetate solvent, b) recovering the crystallinesalt; and c) optionally basifying the salt to form the correspondingfree base.
 9. The method according to claim 8, wherein the solventcomprises up to 6 w-% of water.
 10. Crystalline polymorphic form I of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrilewherein the X-ray diffraction pattern has the following peak positions:2θ angle(°)  8.7  9.5 12.2 15.4 15.9 17.7 18.4 19.2 20.3 21.4 21.8 23.124.6 25.7  27.4.


11. A method for obtaining crystalline polymorphic form I of claim 10which comprises heating optically substantially pure(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrilewhich is a mixture of the polymorphic form I and any other polymorphicform at a temperature of at least 70° C. for a time period necessary forthe formation of pure polymorphic form I.
 12. The method according toclaim 4, wherein the solvent comprises 2-4 w-% of water.
 13. The methodaccording to claim 12, wherein the solvent comprises about 3 w-% ofwater.
 14. The method according to claim 9, wherein the solventcomprises 2-4 w-% of water.
 15. The method according to claim 14,wherein the solvent comprises about 3 w-% of water.
 16. A method forobtaining crystalline polymorphic form I of(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile wherein the X-ray diffraction patternhas the following peak positions: 2θ angle(°)  8.7  9.5 12.2 15.4 15.917.7 18.4 19.2 20.3 21.4 21.8 23.1 24.6 25.7 27.4

which comprises preparing optically substantially pure(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrileaccording to any of claims 1-7 or 13-14.